Daunorubicins/Doxorubicins
Topoisomerase I
A sulforhodamine B assay demonstrates the cytotoxic effects of PNU-159682 (0-500 nM; exposed to the compounds for 1 hour and then cultured in compound-free medium for 72 hours). This was observed in human tumor cell lines. For the cells HT-29, A2780, DU145, EM-2, Jurkat, and CEM, the IC70 values are 0.577 nM, 0.39 nM, 0.128 nM, and 0.081 nM, 0.086 nM, and 0.075 nM, respectively[1]. It works against human tumor cell lines, with IC70 values for MMDX and doxorubicin ranging from 68 nM to 578 nM and 181 nM to 1717 nM, respectively[1]. MMAE is not as effective against NHL cell lines as PNU-159682. In an assay for cell viability, PNU-159682 is antagonistic to BJAB. Luc, WSU-DLCL2, SuDHL4.Luc, Granta-519, and Luc, with corresponding IC50 values of 0.10 nM, 0.020 nM, 0.055 nM, and 0.1 nM. However, MMAE opposes BJAB. Luc, WSU-DLCL2, Granta-519, SuDHL4.Luc, and 0.54 nM, 0.25 nM, 1.19 nM, and 0.25 nM, in that order[2].
PNU-159682 has the potential to create a new class of ADCs and is thousands of times more cytotoxic than doxorubicin. In vitro, PNU159682?to?anti-CD22?antibody (anti-CD22-NMS249) demonstrates potent anti-tumor properties. In vitro viability assays of NHL cell lines, anti-CD22-NMS249 (PNU159682-to-anti-CD22 antibody) is active and 2–20 times more potent than pinatuzumab vedotin; the ADC anti-CD22-NMS249 is against BJAB. The IC50 values of Luc, Granta-519, SuDHL4.Luc, and WSU-DLCL2 are 0.058 nM, 0.030 nM, 0.0221 nM, and 0.01 nM, in that order[3].
The activity of PNU-159682 (100 μM) to inhibit topoisomerase II unknotting is weak. With an IC50 of 25 nM, PNU-159682 exhibits a cytotoxic effect on SKRC-52 cells that express CAIX[4].

A sulforhodamine B assay demonstrates the cytotoxic effects of PNU-159682 (0-500 nM; exposed to the compounds for 1 hour and then cultured in compound-free medium for 72 hours). This was observed in human tumor cell lines. For the cells HT-29, A2780, DU145, EM-2, Jurkat, and CEM, the IC70 values are 0.577 nM, 0.39 nM, 0.128 nM, and 0.081 nM, 0.086 nM, and 0.075 nM, respectively[1]. It works against human tumor cell lines, with IC70 values for MMDX and doxorubicin ranging from 68 nM to 578 nM and 181 nM to 1717 nM, respectively[1]. MMAE is not as effective against NHL cell lines as PNU-159682. In an assay for cell viability, PNU-159682 is antagonistic to BJAB. Luc, WSU-DLCL2, SuDHL4.Luc, Granta-519, and Luc, with corresponding IC50 values of 0.10 nM, 0.020 nM, 0.055 nM, and 0.1 nM. However, MMAE opposes BJAB. Luc, WSU-DLCL2, Granta-519, SuDHL4.Luc, and 0.54 nM, 0.25 nM, 1.19 nM, and 0.25 nM, in that order[2].
PNU-159682 has the potential to create a new class of ADCs and is thousands of times more cytotoxic than doxorubicin. In vitro, PNU159682?to?anti-CD22?antibody (anti-CD22-NMS249) demonstrates potent anti-tumor properties. In vitro viability assays of NHL cell lines, anti-CD22-NMS249 (PNU159682-to-anti-CD22 antibody) is active and 2–20 times more potent than pinatuzumab vedotin; the ADC anti-CD22-NMS249 is against BJAB. The IC50 values of Luc, Granta-519, SuDHL4.Luc, and WSU-DLCL2 are 0.058 nM, 0.030 nM, 0.0221 nM, and 0.01 nM, in that order[3].
The activity of PNU-159682 (100 μM) to inhibit topoisomerase II unknotting is weak. With an IC50 of 25 nM, PNU-159682 exhibits a cytotoxic effect on SKRC-52 cells that express CAIX[4].

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PNU-159682 showed potent cytotoxicity against CAIX-expressing SKRC-52 renal cell carcinoma cells with an IC₅₀ of 0.16 nM. The conjugate 5a (acetazolamide-linked PNU-159682) exhibited reduced in vitro cytotoxicity compared to the free drug, with an IC₅₀ of 25 nM, indicating prodrug formation and lack of efficient cellular internalization. [2]

In the murine L1210 leukemia model, PNU-159682 (single-dose; intravenous; 15 μg/kg) is the maximum tolerated dose. PNU-159682 exhibits enhanced in vivo antitumor activity. PNU-159682's antitumor effect (life span increase of 29%) is similar to that of 90 μg/kg MMDX (life span increase of 36%)[1].
In MX-1 human mammary carcinoma mice, PNU-159682 (i.v. 4 μg/kg; q7dx3; 40 days) exhibits a therapeutic response. Furthermore, four of the seven mice given PNU-159682 show total tumor regression starting on day 39[1].
PNU-159682 can be used to create a new class of ADCs because it is more cytotoxic than doxorubicin. In vivo, PNU159682?to?anti-CD22?antibody (anti-CD22-NMS249) demonstrates potent anti-tumor properties. Mice respond well to the ADC dose (anti-CD22-NMS249; 50 μg/m2 conjugated PNU-159682), which causes less than 10% weight loss[2].
Anti-CD22-NMS249 (single dose; 2 mg/kg) has comparable efficacy to anti-CD22-vc-MMAE in the BJAB.Luc model. AntiCD22-NMS249, at a dose of 2 mg/kg, completely eradicates the tumors (NMS249: 110-134%TGI vs. vc-MMAE: 114-143%TGI). Furthermore, a single 2 mg/kg dose of antiCD22-NMS249 causes three weeks of tumor stasis[1].

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The conjugate 5a (acetazolamide-PNU-159682) administered at 25 nmol/kg showed potent antitumor activity in nude mice bearing SKRC-52 xenografts, while the non-targeted control 5b (devoid of acetazolamide) showed no activity. A second cycle of therapy with 5a did not lead to tumor regression, possibly due to reduced tumor uptake after initial treatment. [2]

Nemorubicin (3'-deamino-3'-[2''(S)-methoxy-4''-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3'',4'-anhydro-[2''(S)-methoxy-3''(R)-oxy-4''-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682 . Experimental design: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively. Results: HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts. Conclusions: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.[1]\n

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\nCorrelation Studies. [1]
\nMMDX (20 μmol/L) was incubated with microsomal fractions from 10 individual human livers; the incubation protocol was the same as that described above. The rates of PNU-159682 formation obtained in these experiments were correlated with several known CYP form-selective catalytic activities evaluated in the same microsomal samples (data provided by BD Gentest except those for nifedipine oxidation and erythromycin N-demethylation). Coefficients of determination (r2) and P values were determined by linear regression analysis.\n

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\nChemical and Immunochemical Inhibition Studies. [1]
\nFormation of PNU-159682 from 20 μmol/L MMDX by pooled HLMs was evaluated in the absence (i.e., control) and presence of known CYP form-selective chemical inhibitors. The following inhibitors were examined at concentrations previously identified as being appropriate to cause CYP form-selective inhibition in HLMs: 7,8-benzoflavone (1 μmol/L, CYP1A2-selective), sulfaphenazole (20 μmol/L, CYP2C9-selective), quinidine (5 μmol/L, CYP2D6-selective), diethyldithiocarbamate (25 μmol/L; CYP2A6/E1-selective), troleandomycin (100 μmol/L, CYP3A-selective) and ketoconazole (1 μmol/L, CYP3A-selective). In experiments with reversible inhibitors, i.e., 7,8-benzoflavone, quinidine, sulfaphenazole, and ketoconazole, the inhibitor was coincubated with the substrate; the incubation protocol was the same as described above. In experiments with mechanism-based inhibitors, i.e., diethyldithiocarbamate and troleandomycin, the inhibitor was preincubated with liver microsomes and NADPH (0.5 mmol) at 37°C for 15 minutes before adding the substrate and additional 0.5 mmol NADPH. The reactions were then conducted as described above.\n
\nImmunochemical inhibition studies were carried out using mouse ascites fluids containing inhibitory MAbs which have been shown to be specific for different human CYP enzymes. Pooled HLMs (0.25 mg microsomal protein/mL; 20 pmol of total CYP) were preincubated with the designated amount of mouse ascites containing anti-CYP MAb (20-140 μg) at 37°C for 5 minutes in 0.3 mol/L Tris (pH 7.4); the reaction was then initiated by the addition of MMDX (final concentration, 20 μmol/L) and NADPH (final concentration, 0.5 mmol/L) in a total volume of 0.2 mL, and conducted as described above. The highest concentration of each MAb used in these trials (i.e., 7 μg ascites protein/pmol of total CYP) was previously shown to be saturating for an appropriate CYP form-specific reaction in HLMs. Control incubations were carried out in the absence of MAb.\n

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\nIncubation of MMDX with cDNA-expressed Human Cytochrome P450 Enzymes [1]
\nIncubations of MMDX with microsomes containing cDNA-expressed CYP enzymes were done as described for HLMs, except that the amount of enzyme used was 50 pmol/mL and incubations were terminated after 60 minutes; substrate concentration was 20 μmol/L. All incubations were done in duplicate. Aliquots of the supernatants from each sample were analyzed for PNU-159682 content by HPLC with fluorescence detection.

Cell Line: Jurkat, CEM, HT-29, A2780, DU145, and EM-2 cells
Concentration: 0-500 nM
Incubation Time: cultivated in compound-free medium for 72 hours after being exposed to PNU-159682 for one hour.
Result: was more potent than doxorubicin by 6,420 to 2,100 fold and MMDX by 2,360 to 790 fold, respectively.
PNU-159682's displayed IC70 values are in the subnanomolar range (0.07-0.58 nM) and significantly less than those found for doxorubicin and MMDX.

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In vitro Cytotoxicity [1]
The cytotoxic effects of doxorubicin, MMDX, and PNU-159682 on adherent tumor cell lines (HT-29, A2780, and DU 145) were evaluated using the sulforhodamine B assay as described by Skehan et al.; the effects of the drugs on the growth of nonadherent tumor cell lines (CEM, Jurkat, and EM-2) were evaluated by counting the surviving cells at the end of the treatment period with a ZM Cell Counter. Exponentially growing cells were seeded 24 hours before treatment and exposed to drugs for 1 hour, after which the medium was withdrawn and cells were incubated in a drug-free medium for 72 hours; control cells were not exposed to the drugs. Within each experiment, determinations were done in six times. IC70 values were then calculated from semilogarithmic concentration-response curves by linear interpolation. Data were expressed as mean ± SE of at least three independent experiments.

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SKRC-52 cells were seeded in 96-well plates at 5,000 cells per well and allowed to grow for 24 hours. The medium was replaced with medium containing serially diluted test compounds. After 72 hours of incubation, cell viability was assessed using MTS reagent, and absorbance was measured at 490 nm. IC₅₀ values were determined using a four-parameter logistic equation. [2]

Animal Model: MX-1 tumor fragments in four- to six-week-old female CD-1 athymic nude mice[1]
Dosage: 4 μg/kg
Administration: Intravenous injection; q7dx3; 40 days
Result: demonstrated anti-cancer properties in human mammary carcinoma xenografts (MX-1) treated with PNU-159682 .

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Disseminated L1210 Leukemia. [1]
Eight-week-old inbred female CD2F1 (BALB/c × DBA/2) were used for evaluation of the therapeutic efficacy of PNU-159682 , in comparison with that of MMDX. Disseminated neoplasia was induced by i.v. injection of 105 L1210 cells; 1 day later, the animals were randomly assigned to an experimental group (n = 10) and received a single i.v. injection of MMDX, PNU-159682 , or saline (control group). Treatment efficacy was evaluated by comparing the median survival time in the treated and control groups, and expressed as increase in life span as follows: % increase in life span = (100 × median survival time of drug treated mice / median survival time of control mice) − 100. Statistical comparison between the groups was made using the nonparametric Mann-Whitney test.

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Subcutaneous MX-1 Human Mammary Adenocarcinoma Xenografts. [1]
Four- to six-week-old female CD-1 athymic nude mice (from Charles River) were used for evaluation of the activity of PNU-159682 against MX-1 human mammary carcinoma xenografts. On day 0, animals (n = 14) were grafted s.c. with MX-1 tumor fragments in the right flank. Eight days later, they were randomly assigned to the drug treatment group or control group (n = 7 mice per group), and treatment was started. PNU-159682 was given i.v. (4 μg/kg) according to a q7dx3 (every 7 days for three doses) schedule; control animals received saline injections. Tumor volume was estimated from measurements done with a caliper using the formula: tumor volume (mm3) = D × d2 / 2; where D and d are the longest and the shortest diameters, respectively. For ethical reasons, control animals were sacrificed on day 21 when the mean tumor volume in the group was ∼2,500 mm3; animals receiving drug treatment were monitored up to day 50, at which point they were sacrificed.

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Female athymic Balb/c nu/nu mice bearing subcutaneous SKRC-52 tumors (average volume 0.1 mL) were used. 5a and 5b were dissolved in sterile PBS containing 1% DMSO and administered intravenously at 25 nmol/kg. Tumor volume and body weight were monitored regularly. [2]

Treatment of mice with compound 5a resulted in reversible weight loss (up to 10%), with weight returning to normal after discontinuation of the drug. The maximum tolerated dose of compound 5a was 50 nmol/kg. [2]

[1]. Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes. Clin Cancer Res. 2005 Feb 15;11(4):1608-17.

[2]. Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma. Mol Cancer Ther. 2016 Dec;15(12):2926-2935.

[3]. Recent advances of antibody drug conjugates for clinical applications. Acta Pharm Sin B. 2020 Sep;10(9):1589-1600.

[4]. Interim data: Phase I/IIa study of EGFR-targeted EDV nanocells carrying cytotoxic drug PNU-159682 (E-EDV-D682) with immunomodulatory adjuvant EDVs carrying α-galactosyl ceramide (EDV-GC) in patients with recurrent, metastatic pancreatic cancer. GASTROINTESTINAL CANCER—GASTROESOPHAGEAL, PANCREATIC, AND HEPATOBILIARY. Journal of Clinical Oncology, Volume 38, Number 15_supplMay 2020

We recently confirmed that the investigational antitumor drug nemomycin (MMDX) can be converted into the active metabolite PNU-159682 via human hepatic cytochrome P450 (CYP) 3A4. This study aims to: (1) investigate the metabolism of MMDX in the liver microsomes of experimental animals (male and female mice, rats, and dogs) to determine whether PNU-159682 is also present in these animals and to identify the CYP enzyme responsible for its generation; (2) compare the metabolism of MMDX in animal and human liver microsomes (HLM) to determine which animal is most closely related to humans; and (3) explore whether the differences in PNU-159682 generation are the cause of previously reported species and sex differences in MMDX host toxicity. Animal metabolism of MMDX is similar in nature to that in human liver microsomes (HLM) because, in all tested species, MMDX is primarily converted to PNU-159682 via a single CYP3A enzyme. However, significant quantitative differences in kinetic parameters were observed between and within species. The V(max) and intrinsic metabolic clearance (CL(int)) values of mice and male rats are closest to those of humans, indicating that these species are the most suitable animal models for studying the biotransformation of MMDX. There is a strong negative correlation between the CL(int) of MMDX and the previously reported LD(50) values of MMDX in animals of the same species, sex, and strain, suggesting that the differences in in vivo toxicity of MMDX are likely due to sex and species differences in the degree of PNU-159682 production. Source: Biochem Pharmacol. Sep 15, 2008; 76(6):784-95.

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Objective: Nemorubicin (3'-deamino-3'-[2''(S)-methoxy-4''-morpholino]doxacin; MMDX) is an investigational drug currently undergoing a phase II/III clinical trial for the treatment of hepatocellular carcinoma. Recently, a bioactivated product of MMDX, namely 3'-deamino-3'',4'-dehydrat-[2''(S)-methoxy-3''(R)-oxy-4''-morpholinyl]doxorubicin (PNU-159682), was discovered in the incubation medium of MMDX and rat liver microsomes supplemented with NADPH. This study aimed to obtain information on the biotransformation of MMDX into PNU-159682 in humans and to explore the antitumor activity of PNU-159682. Experimental Design: This study used human liver microsomes (HLM) and genetically engineered cell lines expressing specific human cytochrome P450 (CYP) to study the biotransformation of MMDX. In addition, we also used in vitro cultured human tumor cell lines and tumor-bearing mouse models to detect the cytotoxicity and antitumor activity of PNU-159682. Results: HLM converted MMDX into a major metabolite whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of the synthesized PNU-159682. In HLM libraries from 10 donors, the rate of PNU-159682 production was significantly correlated with the activities of three different CYP3A-mediated processes. Traromycin and ketoconazole, both CYP3A inhibitors, significantly reduced PNU-159682 production in human liver microsomes (HLM); this reaction was also inhibited in a concentration-dependent manner by CYP3A4/5 monoclonal antibodies. Of the 10 cDNAs expressed by CYP3A4 detected, only CYP3A4 produced PNU-159682. Furthermore, PNU-159682 exhibited more significant cytotoxicity in vitro than MMDX and doxorubicin, and was effective in both of the tested in vivo tumor models (disseminated mouse L1210 leukemia and MX-1 human breast cancer xenograft). Conclusion: CYP3A4 is the main CYP enzyme in the human liver that can convert MMDX into the more cytotoxic metabolite PNU-159682, which retains antitumor activity in vivo. [1]

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In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, leading to unnecessary toxicity and hindering dose escalation to a therapeutically effective regimen. This paper shows that acetazolamide derivatives can bind to carbonic anhydrase IX (CAIX) on the surface of renal cancer cells, thereby selectively delivering the payload to the lesion site without damaging normal organs. Biodistribution studies in tumor-bearing mice showed that acetazolamide derivatives with technetium-99m chelates or red fluorophores as payloads preferentially accumulate in tumors at doses up to 560 nmol/kg. The percentage of the injected dose per gram in the tumor was dose-dependent, with the optimal tumor/organ ratio at a dose of 140 nmol/kg and a tumor/blood ratio of 80:1 at 6 hours. Acetazolamide, conjugated with a potent cytotoxic drug via a dipeptide linker, exhibited potent antitumor activity in nude mice carrying SKRC-52 renal cell carcinoma, while drug derivatives without the acetazolamide moiety did not show any detectable anticancer activity at the same dose. Tumor regression observed using non-internalizing ligands and different cytotoxic moieties (MMAE and PNU-159682) suggests that their mechanisms of action are largely the same: the drug selectively accumulates on tumor cells, followed by the release of the cytotoxic payload through extracellular protein hydrolysis at the tumor site, and finally the drug is internalized by the tumor cells. Acetazolamide-based drug conjugates may represent a promising class of targeted therapies for the treatment of metastatic renal cell carcinoma, as most human clear cell renal cell carcinomas are strongly positive for CAIX. Mol Cancer Ther; 15(12); 2926-35.[2]

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Antibody-drug conjugates (ADCs) are typically composed of humanized antibodies and small molecule drugs linked by chemical linkers. After decades of preclinical and clinical research, a range of antibody-drug conjugates (ADCs) have been widely used to treat specific types of cancer, such as brentuximab (Adcetris®) for relapsed Hodgkin's lymphoma and systemic anaplastic large cell lymphoma, gemtuzumab (Mylotarg®) for acute myeloid leukemia, ado-trastuzumab (Kadcyla®) and inotuzumab ozogamicin (Besponsa®) for HER2-positive metastatic breast cancer, and more recently, polatuzumab vedotin-piiq (Polivy®) for B-cell malignancies. To date, more than 80 ADCs are in various stages of clinical trials across approximately 600 trials. This review summarizes the key elements of antibody-drug conjugates (ADCs), highlighting the latest advancements in ADCs, important lessons learned from clinical data, and future directions. [3]

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Background: Targeted EDV nanocells loaded with doxorubicin and microRNA16a have shown good safety profiles in a phase I clinical trial in recurrent glioma and mesothelioma. This study plans to conduct a safety analysis of an ongoing first-in-human open-label phase I/IIa clinical trial in patients with refractory metastatic pancreatic cancer to evaluate the safety, biological activity, and clinical activity of EGFR-targeted EDV nanocells loaded with the cytotoxic drug PNU-159682 (designed to overcome resistance) in combination with EDV nanocells loaded with the immunomodulatory adjuvant α-galactosylceramide (designed to stimulate antitumor immune responses). Methods: Nine patients with advanced pancreatic cancer were enrolled in a dose-escalation phase to evaluate the safety of the combination therapy. The dose was gradually increased from 2 x 10⁹ EDV/dose to a maximum dose of 7 x 10⁹ EDV/dose at week 7, followed by administration of the maximum dose achieved in cycle 1. Tumor response was assessed using the iRECIST criteria after each cycle, and blood samples were collected at each cycle for cytokine and peripheral blood mononuclear cell (PBMC) analysis. Results: The combined EDV was well tolerated, with no dose-limiting toxicities (DLTs) or drug-related serious adverse events (SAEs). A small number of patients experienced Grade 1 infusion responses, which resolved rapidly with supportive care. Of the 9 patients, 8 achieved partial response (PR) or stable disease (SD) at 8 weeks (89% clinical benefit rate), and of the 5 evaluable patients, 4 achieved confirmed response at 4 months (80%), with 2 patients having a response duration exceeding 6 months. Exploratory analysis showed elevated IFN-α and IFN-γ levels in almost all evaluable patients (6/8). In addition, we observed an increase in the number of CD8+ T cells (2/8), iNKT cells, dendritic cells and NK cells (3/8), and a decrease in the number of exhausted CD8+ T cells (3/8), suggesting that both innate and adaptive immune responses were activated. Conclusion: EDV carrying cytotoxic drugs and immune adjuvants is safe and well tolerated. Early signals indicate durable efficacy, which may be related to the generation of innate and adaptive immune responses and cytotoxic effects on drug-resistant tumor cells. A Phase IIa study plans to recruit 35 more patients to further evaluate its safety and antitumor efficacy. Clinical trial information: ACTRN12619000385145. [4] PNU-159682 is described as a metabolite of nimomycin. It is conjugated to acetazolamide via a valine-citrulline dipeptide linker for targeted delivery to CAIX-positive renal cell carcinoma. The conjugate is designed to be cleaved extracellularly by proteases such as cathepsin B, and then the drug diffuses into the tumor cells. [2]

C32H35NO13

641.6192

641.21

C, 61.24; H, 5.94; N, 2.23; O, 30.59

202350-68-3

PNU-159682;202350-68-3

9874188

Reddish Brown to red solid powder

1.6±0.1 g/cm3

838.5±65.0 °C at 760 mmHg

460.9±34.3 °C

0.0±3.2 mmHg at 25°C

1.691

6.18

4

14

6

46

1200

8

C[C@H]1[C@@H]2[C@H](C[C@@H](O1)O[C@H]3C[C@@](CC4=C3C(=C5C(=C4O)C(=O)C6=C(C5=O)C(=CC=C6)OC)O)(C(=O)CO)O)N7CCO[C@@H]([C@H]7O2)OC

SLURUCSFDHKXFR-WWMWMSKMSA-N

InChI=1S/C32H35NO13/c1-13-29-16(33-7-8-43-31(42-3)30(33)46-29)9-20(44-13)45-18-11-32(40,19(35)12-34)10-15-22(18)28(39)24-23(26(15)37)25(36)14-5-4-6-17(41-2)21(14)27(24)38/h4-6,13,16,18,20,29-31,34,37,39-40H,7-12H2,1-3H3/t13-,16-,18-,20-,29+,30+,31-,32-/m0/s1

(7S,9S)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-7-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,9,10,12-tetrahydrotetracen-5(8H)-one

PNU-159682; PNU 159682; PNU159682； PNU-159682; 202350-68-3; UNII-CQ5A9ZNT7C; CQ5A9ZNT7C; (8S,10S)-6,8,11-Trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione; (8S,10S)-7,8,9,10-Tetrahydro-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-octahydro-9-methoxy-1-methyl-1H-pyrano(4',3':4,5)oxazolo(2,3-C)(1,4)oxazin-3-yl)oxy)-5,12-naphthacenedione;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~155.86 mM）

10% DMSO+ 40% PEG300+ 5% Tween-80+ 45% saline: ≥ 2.5 mg/mL (3.90 mM) (Please use freshly prepared in vivo formulations for optimal results.)